Association of plasma and CSF cytochrome P450, soluble epoxide hydrolase and ethanolamides metabolism with Alzheimer’s disease

Background Alzheimer’s disease, cardiovascular disease and other cardiometabolic disorders may share inflammatory origins. Lipid mediators, including oxylipins, endocannabinoids, bile acids and steroids regulate inflammation, energy metabolism and cell proliferation with well-established involvement in cardiometabolic diseases. However, their roles in Alzheimer’s disease and their potential as biomarkers are poorly understood. Here we describe the analysis of plasma and cerebrospinal fluid lipid mediators in a case-control comparison of individuals with Alzheimer’s disease and healthy controls to investigate these knowledge gaps. Methods Lipid mediators were measured using targeted quantitative mass spectrometry. Data were analyzed using analysis of covariates, adjusting for sex, age, and ethnicity. Partial least square discriminant analysis identified plasma and cerebrospinal fluid lipid mediator discriminates of Alzheimer’s disease. Alzheimer’s disease predictive models were constructed using machine learning combined with stepwise logistic regression. Results In both plasma and cerebrospinal fluid, individuals with Alzheimer’s disease had elevated cytochrome P450/soluble epoxide hydrolase pathway components and decreased fatty acid ethanolamides compared to healthy controls. Circulating metabolites of soluble epoxide hydrolase and ethanolamides provide Alzheimer’s disease predictors with areas under receiver operator characteristic curves ranging from 0.82 to 0.92 for cerebrospinal fluid and plasma metabolites, respectively. Conclusions Previous studies report Alzheimer’s disease-associated soluble epoxide hydrolase upregulation in the brain and that endocannabinoid metabolism provides an adaptive response to neuroinflammation. This study supports the involvement of P450-dependent and endocannabinoid metabolism in Alzheimer’s disease, yielding potential biomarkers of the disorder. The results further suggest that combined pharmacological intervention targeting both metabolic pathways may have therapeutic benefits for Alzheimer’s disease.